Systemic microbial infection and release of microbial products induces the hyperactivation of host immune cells, subsequently generating an exacerbated inflammatory response. Sepsis may result in the inability of the immune system to control this inflammation, and can end in tissue injury, increased vascular permeability and it can cause multi-organ failure and shock (septic shock).
Sepsis can result from many causes but is typically triggered by pneumonia, trauma, surgery, and burns or by conditions such as cancer or AIDS. Sepsis usually begins with tremor, fever, falling blood pressure (septic shock), rapid breathing, rapid heart rate, and skin lesions. Within hours, sepsis may cause spontaneous clotting in blood vessels, severe hypotension, multiple organ failure, shock, gangrene and eventually death. Sepsis causes high morbidity and mortality in humans and other animals (mortality of up to 70% in septic patients). In the United States and Europe, 1.5 million people develop sepsis annually. 30% of these patients die after one month and a 20% after six months. In the United States, sepsis is the 10th cause of death, which represents a mortality higher than those caused by infarct, breast cancer or lung cancer.
The most important intervention in sepsis is quick diagnosis and treatment. Diagnosing sepsis can be difficult. Some of its symptoms, such as fever, rapid pulse, and respiratory difficulty occur frequently and can be confused as being due to other disorders. Patients diagnosed with severe sepsis are usually placed in the intensive care unit (ICU) of the hospital for special treatment. The first line of treatment is to identify and eliminate the underlying infection with anti-infection agents or surgery to drain the site of infection. Current methods for treating sepsis include antibacterials, antibodies, peptides, and a recombinant human activated protein C named drotecogin alpha, marketed by Eli Lilly as Xigris®. However, drotecogin alpha only reduces the mortality associated with severe sepsis in a 5%, and not all the patients respond positively to this drug. Steroids have also been recently shown to be valuable in patients with septic shock. The doctor also administers intravenous fluids to prevent blood pressure from dropping too much. In some cases, vasopressor medications (which constrict blood vessels) are needed to achieve an adequate blood pressure. Finally, if organ failures occur, appropriate supportive care is provided (e.g., dialysis for kidney failure, mechanical ventilation for respiratory failure, etc.).
Due to the high level of redundancy regarding molecular mediators in the sepsis response, new approaches are likely to focus on intervening at multiple points in the sepsis cascade. Some drug candidates in early phase of development are a Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) receptor antagonist (Merck & Co Inc and BioXell SpA); a super-antigen antagonist (Atox Bio Ltd.), a short peptide which blocks the action of a family of deadly bacterial toxins produced by Staphylococcus aureus and Streptococcus pyogenes, termed as super-antigens; Immune Regulating Hormone (IRH, Hollis-Eden Pharmaceuticals Inc.), an autoimmune and anti-inflammatory drug which controls immune system and metabolic functions; and an Adenosine A1 receptor antagonist as a treatment for Gram-negative septicemia (Endacea Inc.). Other molecules under development are Toll-like Receptor-4 antagonists (Takeda and Eisai); anti-TNF-alfa polyclonal antibody fragment (Protherics); bovine intestine-derived alkaline phosphatase (AM-Pharma); Norathiol (Medinox), which neutralizes nitric oxide; and transgenic antithrombin III ATryn® (GTC Biotherapeutics) which received marketing approval from European regulatory authorities in 2006 and it is in late-stage clinical trials in the United States.
Other approaches have been proposed for treating sepsis, such as: anti-IL-8 antibodies (US Patent Publication No. 20030021783A), anti-IL-18 antibodies (US 20030008822A), anti-C5a antibodies and C-terminal truncated C5a peptides (US 20020165138A), chemokines and chemokine fragments (US 20020155094A), a combination of protein C and BPI antibodies (US 20020044929A), COX-2 inhibitors (US 20020006915A), algae lipopolysaccharides (U.S. Pat. No. 6,534,648) and using an antibody to TNF-α and an antibody to bacterial lipopolysaccharide (U.S. Pat. No. 6,315,999). However, despite the major advances of the past several decades in the treatment of serious infections, the incidence of sepsis and mortality due to sepsis continue to increase. Therefore, it seems desirable to provide new methods and compositions for the prevention and treatment of infectious diseases and of inflammatory conditions related to these infectious diseases.